The present invention relates to hydrobromide salts of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenytsulphonylethyl)-1H-indole having the formula (I): 
In a preferred aspect, the invention relates to a particular polymorphic form, hereinafter referred to as the xcex1-form, of the hydrobromide salt identified above. In addition it relates to an intermediate polymorphic form, hereinafter referred to as the xcex2-form, of the said hydrobromide salt, to processes for the preparation of the xcex1- and xcex2-forms, to pharmaceutical compositions containing the xcex1-form, and to uses of the xcex1-form in medicine.
WO-A-92/06973 relates to a series of 3,5disubstituted indoles and pharmaceutically acceptable salts thereof useful in the treatment of migraine and other disorders. Examples cited therein of such salts are the hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate or bisulphate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulphonate and pamoate. Specifically disclosed therein is 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5(2-phenylsulphonylethyl)-1H-indole and its hemisuocinate salt, the latter being characterised as a non-crystalline foam. Further studies have confirmed that this salt is unsuitable for pharmaceutical formulation, as numerous attempts to obtain it in a form which has the properties required for formulation have been unsuccessful.
Thus the problem addressed by the present invention is the provision of a pharmaceutically acceptable salt of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5(2-phenylsulphonylethyl)-1H-indole which can be efficiently processed to provide stable and effective formulations of the drug, in particular solid and compressible dosage forms. Such dosage forms include conventional-release oral tablets, controlled-release (matrix) tablets, fast-dissolving tablets (e.g. freeze-dried), sublingual tablets, buccal tablets, oral powder- and granule-filled capsules, powders for reconstituted suspensions, conventional and controlled-release multiparticulate systems filled into capsules or compressed into tablets, lozenges, dragees, suppositories, pessaries, solid implants, lyophile plugs, nanoparticles and microparticles and powder for suspension and nasal delivery, and dry inhalation systems.
Important criteria to be satisfied are, inter alia, that the selected salt should be crystalline, of suitable melting point, non-hygroscopic, compressible and possess solid-state stability, coupled with acceptable solubility and dissolution behaviour.
This problem has been solved by the surprising finding of a novel xcex1-form of the hydrobromide salt of formula (I) which meets the above requirements; thus it is proeminently suitable for providing pharmaceutical formulations in solid dosage form, in particular for oral, buccal and sublingual administration.
The first step in approaching the solution to the problem was the generation of an acid addition salt of the monoacidic base, 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole, which is both crystalline and of high enough melting point ( greater than ca. 130xc2x0 C.) to have the potential to undergo pharmaceutical processing during solid dosage form manufacture and compaction.
Attempts were made to obtain a suitable form of the following salts: hydrochloride, hydrobromide, hemisulphate, bisulphate, nitrate, acid phosphate, phosphate, methanesulphonate, benzenesulphonate, p-toluenesulphonate, (+)-camphorsulphonate, acetate, benzoate, citrate, hemifumarate, fumarate, hemimaleate, maleate, hemisuccinate, succinate, hemi-L-tartrate, L-tartrate, hemi-D-tartrate, D-tanrate, L-lactate, (R)-(xe2x88x92)-mandelate, hippurate, hemiphthalate, phthalate and hemiterephthalate.
Of these thirty possible salts, only four could be obtained as crystalline solids, namely the hemisulphate, hydrochloride, hydrobromide and benzenesulphonate; the remainder were obtained as non-crystalline/low or non-sharp melting/sticky solids, gums, glasses, froths, resins or oils. Moreover, of the four crystalline salts, the benzenesulphonate proved to have an insufficiently high melting point (m.p.) of 74-75xc2x0 C. Thus only the hemisulphate, hydrochloride and hydrobromide salts were progressed to more detailed studies.
Hemisulphate Salt
The hemisulphate salt initially isolated (m.p. 145-147xc2x0 C.), designated the xcex2-form, does not show a clean single-melting endotherm when examined by differential scanning calorimetry (DSC) but rather a complex trace indicative of polymorphic transition. Indeed, this xcex2-form is very hygroscopic at relative humidities (RH) higher than 50% and, under certain conditions, water uptake can cause polymorphic conversion to an alternative form, designated the xcex1-form, of m.p. 185xc2x0 C., or even degradation. Furthermore, the xcex2-form undergoes a colour change on compression and causes punch-filming during tabletting and thus, for a variety of reasons, its physicochemical properties render it unsuitable for the development of solid dosage forms.
Whilst the xcex1-form of the hemisulphate salt does not display solid state instability associated with water uptake, it is extremely hygroscopic nevertheless and therefore also unsuitable for development because of consequential difficulties with variable flow properties, and bulk and dosage form instability which precludes, inter alia, accurate assignment of drug activity.
Hydrochloride Salt
Depending on the solvent used as reaction medium and for crystallisation, either of two forms of the hydrochloride salt can be obtained. The first of these to be isolated and characterised, designated the xcex2-form, of m.p. 125-129xc2x0 C. (broad endotherm at 135xc2x0 C. at a scan rate of 20xc2x0 C./min. by DSC, but no dehydration endotherms apparent), was found to have a water content of 4.42% (1.08 mol) by Karl Fischer titrimetry (KFT). However, although hygroscopicity studies revealed that the xcex2-form does not display solid state instability, it was excluded from further development by its behaviour during compression studies in which melting and sticking of the disk to the punches were observed, thus reinforcing the requirement for a higher melting solid.
The alternative hydrochloride salt, designated the xcex1-form, showed a major, sharp endotherm at 165xc2x0 C. by DSC (scan rate 20xc2x0 C./min.). Determination of its hygroscopicity profile revealed that after seven days at a temperature (T) of 40xc2x0 C. and RH of 75%, unlike the xcex2-form, a significant amount of water had been taken up. This water uptake was found to be associated with changes in the DSC trace which demonstrated that, at least under these humidity conditions, the anhydrous xcex1-form converts to the hydrated xcex2-form. Thus pharmaceutical development of the xcex1-form is also precluded by inadequate physical stability.
Hydrobromide Salt
The hydrobromide salt is also isolable in one of two forms, depending on the preparative conditions employed. The lower melting form, designated the xcex2-form, was found not to be a viable option for the development of a solid dosage form because, when attempts are made to improve its quality, it undergoes polymorphic conversion to a higher melting form, designated the xcex1-form.
However, by contrast, the novel xcex1-form of the hydrobromide salt of formula (I) was found to be unique in unexpectedly possessing the combination of properties required to enable the efficient development of solid dosage forms, namely those of crystallinity, sufficiently high m.p., lack of hygroscopicity, solid-state stability, compressibility and lack of polymorphic conversion, together with satisfactory solubility and dissolution rate profiles.
The present invention therefore provides a crystalline, polymorphic xcex1-form of a hydrobromide salt of formula (I), whose infra-red (IR) spectrum as a mull in nujol shows significant absorption bands at xcexd=3371, 3293, 2713, 2524, 1419, 1343, 1307, 1264, 1151, 1086, 1020, 1008, 999, 922, 900, 805, 758, 740, 728, 689, 672, 652, 640, 598, 581, 573, 531, 498, 465, 457, 443, 428, 422, 414 and 399 cmxe2x88x921.
The xcex1-form is further characterised by its powder X-ray diffraction (PXRD) pattern obtained using copper radiation filtered with a graphite monochromator (xcex=0.15405 nm) which shows main peaks at 9.7, 10.7, 15.9, 16.5, 17.8, 18.3, 19.3, 19.8, 20.1, 21.2, 24.4, 25.5, 25.8, 26.7, 27.6 and 29.4 degrees 2xcex8.
The xcex1-form is yet further characterised by its differential scanning calorimetry (DSC) trace which shows a sharp endotherm at 176.5xc2x0 C. at a scan rate of 20xc2x0 C./min.
The invention also provides a crystalline, polymorphic xcex2-form of a hydrobromide salt of formula (I), which can be used as an intermediate in the preparation of the xcex1-form. Its IR spectrum as a mull in nujol shows significant absorption bands at xcexd=3239, 2672, 2656, 2632, 1409, 1366, 1351, 1334, 1303, 1293, 1152, 1138, 1122, 1098, 1086, 791, 771, 746, 688, 634, 557, 528, 484, 476, 469, 463, 455, 432, 424, 413 and 401 cmxe2x88x921.
The xcex2-form is further characterised by its PXRD pattern obtained using copper radiation filtered with a graphite monochromator (xcex=0.15405 nm) which shows main peaks at 11.0, 17.2, 19.2, 20.1, 21.6, 22.6, 23.6 and 24.8 degrees 2xcex8.
The xcex2-form is yet further characterised by its DSC trace which shows a sharp endotherm at 154.8xc2x0 C. at a scan rate of 20xc2x0 C./min.
The invention further provides processes for the preparation of the xcex1-form of a compound of formula (I), as illustrated by the following.
(A)
Treatment of a solution of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2phenylsulphonylethyl)-1H-indole in a suitable solvent, preferably acetone, at room temperature, with an aqueous solution of hydrogen bromide, followed by crystallisation of the isolated crude oil from a suitable solvent, preferably 2-propanol, affords the xcex1-form of the required hydrobromide salt.
(B)
Treatment of a solution of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole in a suitable solvent, preferably acetone or an ether solvent such as tetrahydrofuran or 1,2-dimethoxyethane, more preferably 1,2-dimethoxyethane, at from 0 to 10xc2x0 C., with an aqueous solution of hydrogen bromide, furnishes the xcex2-form of the required hydrobromide salt.
Crystallisation of the xcex2-form from a suitable solvent, preferably aqueous acetone, followed by slurrying of the resulting mixture, gives the desired xcex1-form.
(C)
Treatment of a solution of 3N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole in a suitable solvent, preferably acetone, at from 0 to 5xc2x0 C. with an aqueous solution of hydrogen bromide and then slurrying of the reaction mixture, optionally followed by heating under reflux, cooling and further slurrying, provides the required xcex1-form.
As previously mentioned, WO-A-92/06973 discloses 3(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole and pharmaceutically acceptable salts thereof for the treatment of migraine and other disorders (incorporated herein by reference). Thus the present invention also relates to pharmaceutical compositions containing the xcex1-form of the hydrobromide salt thereof, uses of the xcex1-form as a medicament and for the manufacture of a medicament for the treatment of migraine and said other disorders, and a method of treating a mammal having migraine or any of said other disorders with the xcex1-form.
The in vitro evaluation of the peripheral 5-HT, receptor agonist activity of the xcex1-form can be carried out by testing the extent to which it mimics sumatriptan in contracting the isolated dog saphenous vein strip (P. P. A. Humphrey et al., Brit. J. Pharmacol., 1988, 94, 1123). This effect can be blocked by methiothepin, a known 5-HT antagonist. Sumatriptan is known to be useful in the treatment of migraine and produces a selective increase in carotid vascular resistance in the anaesthetized dog and a consequent decrease in carotid arterial blood flow. It has been suggested (W. Feniuk et al., Brit. J. Pharmacol., 1989, 96, 83) that this is the basis of its efficacy.
The central 5-HT, agonist activity of the xcex1-form can be measured in in vitro receptor binding assays as described for the 5-HT1A receptor, using rat cortex as the receptor source and [3H]8-OH-DPAT as the radioligand (D. Hoyer et al., Europ. J. Pharmacol., 1985, 118, 13), and as described for the 5-HT1D receptor, using bovine caudate as the receptor source and [3H]5-HT as the radioligand (R. E. Heuring and S. J. Peroutka, J. Neuroscience, 1987, 7, 894).
In therapy, the xcex1-form of the hydrobromide salt of formula (I) can be administered alone, but will generally be administered in admixture with pharmaceutically acceptable excipients, including glidants, disintegrants and lubricants, selected with regard to the intended route of administration and standard pharmaceutical practice. In particular, it may be administered orally in the form of tablets, dragees or lozenges containing excipients such as starch or lactose, or in capsules, ovules or implants, either alone or in admixture with excipients. For buccal or sublingual administration, it may be administered in the form of tablets, dragees or lozenges which can be formulated in a conventional manner.
For oral, buccal or sublingual administration to patients, the daily dosage level of the xcex1-form of the salt of formula (I) will be from 0.01 mg to 20 mg/Kg (in single or divided doses). Thus tablets or capsules will contain from 0.5 mg to 0.5 g of active compound for administration singly, or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Thus the invention provides a pharmaceutical composition comprising the xcex1-form of a compound of formula (I) together with a pharmaceutically acceptable diluent or carrier.
The invention also provides the xcex1-form of a compound of formula (I), or a pharmaceutical composition thereof, for use as a medicament.
The invention further includes the use of the xcex1-form of a compound of formula (I), or a pharmaceutical composition thereof, both for the manufacture of a medicament for the curative or prophylactic treatment of migraine or an associated condition such as cluster headache, chronic paroxysmal hemicrania or headache associated with a vascular disorder, or of depression, anxiety, an eating disorder, obesity, drug abuse, hypertension or emesis, and also for the manufacture of a medicament for the curative or prophylactic treatment of a medical condition for which a selective agonist of 5-HT1 receptors is indicated.
In a further aspect, the invention provides both a method of treating a human being to cure or prevent migraine or an associated condition such as cluster headache, chronic paroxysmal hemicrania or headache associated with a vascular disorder, or depression, anxiety, an eating disorder, obesity, drug abuse, hypertension or emesis, and also a method of treating a human being to cure or prevent a medical condition for which a selective agonist of 5-HT1 receptors is indicated, which comprises administering to said human being an effective amount of the xcex1-form of a compound of formula (I), or a pharmaceutical composition thereof.